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Pathophysiology of Subarachnoid Hemorrhage, Early Brain Injury, and Delayed Cerebral Ischemia
Introduction
Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease that occurs after rupture of an intracranial aneurysm, promoting hemorrhage into the subarachnoid space. This leads to impairment of brain perfusion and function, contributing to brain injury after SAH. It has a complex, multisystem, and multifaceted pathogenesis. Intracranial aneurysms may be present in 2–3% of the population with an annual risk of rupture about 0.7–4% . Although SAH counts for only 5% of all strokes, its burden to individuals and society is significant.
The pathophysiological mechanisms of SAH involve early brain injury (EBI) and delayed cerebral ischemia (DCI), including cerebral vasospasm. Immediately after SAH, early brain injury occurs, lasting up to 72 h. Several mechanisms contribute to EBI pathogenesis. These include cell death signaling, inflammatory response, oxidative stress, excitotoxicity, microcirculatory dysfunction, microthrombosis, and cortical spreading depolarization. EBI and DCI are suggested to be linked due to common pathogenic pathways and direct interaction. Both lead to focal neurological and/or cognitive deficits after SAH. Despite advances in experimental research to decrease the effects of SAH, brain injury remains the major cause of death and disability in patients with SAH. There is no sufficient treatment of SAH and its devastating consequences known so far.
Aneurysm Formation
There are three layers in the blood vessel that act to promote integrity and functionality. The outermost layer, tunica externa, comprises connective tissue providing protection for the vessel. The tunica media is composed of smooth muscle cells and elastic tissue that is responsible for autoregulation of cerebral blood flow. Endothelial cells make up the tunica interna, sensing the shear stress due to blood flow over their surface. Neuronal signaling to the surrounding connective tissue and smooth muscle allows the vessel to adapt its diameter according to blood flow.
Aneurysm formation occurs with an initial vascular lesion after interaction of specific biological, physical, and external factors. A tangential force imposed on the vessel wall by blood flow creates aneurysms, or dilations of the vessel wall. This force, called the wall shear stress, along with two other forces, impulse and pressure, encompasses the hemodynamic factors associated with vessel wall degeneration. The endothelium is the first to be damaged by pressure and shear stress from circulating blood. It senses changes in wall stress and adapts the lumen diameter according to the level of wall shear stress to maintain physiology and determine the overall remodeling process. Vascular remodeling influences the progress and growth of the aneurysm. Thus excessive levels of wall shear stress induce focal injury and denude the endothelial barrier leading to intracranial aneurysm formation. Compared with normal intracranial arteries, the aneurysm wall has a thinner tunica media, and lacks organized vascular structure as well as intact internal elastic lamina. As the intracranial aneurysm progresses, the endothelium changes and alters the blood flow. The aneurysm wall subsequently undergoes a process of constant remodeling. With aging and exposure to hemodynamic stress, layers of fibrous tissue develop between the endothelium and the internal elastic lamina, affecting the capacity of the vessel wall to respond .
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